A Review of In Silico and In Vitro Approaches in the Fight Against Carbapenem‐Resistant Enterobacterales

• Published in: Journal of clinical laboratory analysis Vol. 39; no. 9; pp. e70018 - n/a
• Main Authors: Absar, Muhammad, Zaidah, Abdul Rahman, Mahmood, Amer, Ahmad, Sajjad, Ejaz, Hasan, Ahmed, Naveed, Nik Hashim, Nik Haszroel Hysham, Yean, Chan Yean
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2025; John Wiley and Sons Inc
• Subjects: Anti-Bacterial Agents - pharmacology; Antimicrobial agents; antimicrobial discovery; Antimicrobial resistance; Carbapenem-Resistant Enterobacteriaceae - drug effects; Carbapenems; Carbapenems - pharmacology; Chromosomes; computational pharmacology; Computer applications; Computer Simulation; CRE; Drug discovery; Drug Discovery - methods; Enterobacterales; Enterobacteriaceae Infections - drug therapy; Enterobacteriaceae Infections - microbiology; Humans; in silico validation; Nosocomial infections; Plasmids; R&D; Research & development; Review; virtual screening; in silico validation; computational pharmacology; Enterobacterales; antimicrobial discovery; virtual screening; CRE
• ISSN: 0887-8013; 1098-2825; 1098-2825
• DOI: 10.1002/jcla.70018

ABSTRACT Objectives The rise in carbapenem‐resistant Enterobacterales (CRE) has reinforced the global quest for developing effective therapeutics. Traditional drug discovery approaches have been inadequate in overcoming this challenge due to their resource and time constraints. Methods English literature was searched by structured queries related to our review between January 1, 2020, and December 31, 2024. Results The key resistance mechanisms in CRE, such as enzymatic hydrolysis, decreased permeability, and efflux pump overexpression, have been examined in this review. Computational technologies have become pivotal in discovering novel antimicrobial agents with improved accuracy and efficiency. Besides this, the review highlights the advances in structure‐ and ligand‐based drug discovery approaches for identifying potential drugs against CRE. Recent studies demonstrating the use of such in silico techniques to develop targeted drugs against CRE have also been explored. Moreover, this review also underscores the significance of integrating both in silico and in vitro techniques to counter resistance in Enterobacterales, supported by the latest studies. However, these promising computational technologies have a few major drawbacks, such as a lack of standardized parameterization, potentially false positives, and the complexity of effective clinical translations. The drug regulatory barriers also restrict the progress of new antimicrobials for market approval. Conclusion The use of computational technologies for antimicrobial inhibitor discovery is gaining popularity, and it can be expedited by refining computational techniques and integrating them with reliable in vitro validation. The use of innovative hybrid in silico and in vitro technologies is the need of the hour to tackle CRE and mitigate the global threat of antimicrobial resistance. This review highlights computational approaches for discovering antimicrobials against carbapenem‐resistant Enterobacterales. It outlines methods like pharmacophore modeling, molecular docking, and absorption, distribution, metabolism, and excretion–toxicity (ADMET) analysis, integrated with in vitro assays, to identify and validate potential drugs. Challenges and future perspectives in translating these findings into clinical success are also discussed.